Summary (from Parent Award UG3/UH3 TR002158) Chronic kidney disease is a public health problem affecting more than 30 million people in the US adult population, is the 9th leading cause of death, and accounts for ~27% of Medicare costs. Few drugs have been proven to slow the progression of kidney disease, lower mortality rates, or improve quality of life. New strategies targeting the early stages of these underlying diseases are fundamentally important to improve outcomes and patient care. To catalyze the development of drugs that are safe and effective for treating kidney diseases, during the UH3 phase we plan to fill a critical need to be able to model human kidney diseases and injury in vitro during preclinical drug development. This will be accomplished using a three-dimensional flow directed ?kidney-on-a-chip? microphysiological system populated with human kidney cells, which has been extensively validated with functional characterization of key component structures of the proximal tubule and the peritubular microvascular network. Our platforms allow for precise control of cellular composition, extracellular matrix, and vascular and tubular geometry and flow. We intend to fully accomplish all initially proposed UH3 Milestones and Specific Aim, as outlined in the original grant submission without revision or change: Specific Aim: To demonstrate that multiple rare and monogenetic human kidney disease models in a microphysiological system have functional utility for understanding disease biology, assessing efficacy and toxicity of candidate drugs, and establishing a preclinical foundation that can inform clinical trial design. Milestone 1: Successfully demonstrate that novel candidate therapeutic drugs or biologics can significantly reduce the quantitative rate of cyst formation and/or improve ciliary function in a MPS human kidney model of polycystic kidney disease. Milestone 2: Successfully demonstrate that novel candidate therapeutic drugs or biologics can prevent the development of, or reduce the severity of, thrombotic microangiopathy in a MPS human kidney model. Milestone 3: Successfully demonstrate that novel candidate therapeutic drugs or biologics can quantitatively reduce the severity of aristolochic acid induced kidney damage in a MPS human kidney model. Milestone 4: Successfully demonstrate that novel candidate therapeutic drugs or biologics can reduce the effects of homozygous APO-L1 risk alleles on the development of kidney injury in a MPS human kidney model. Milestone 5: Cross validate MPS disease model endpoints from Milestones 1-4 with clinical endpoints. Milestone 6: Establish translatable pharmacodynamics with target engagement biomarkers from the MPS disease models in Milestones 1-4. Our investigative team has already proven to be highly productive and successful in establishing the utility of the ?human kidney on a chip?, with field-leading expertise needed to address the required technical and experimental challenges.